Sulfur containing derivative of isonicotinic acid hydrazide



SULFUR CONTAINING DERWATIVE F ISONIC- OTINIC ACID nvnaazmn Otto Zima,Darmstadt Eberstadt, and Fritz von Werder,

Dannstadt, Germany, assignors to E. Merck Aklieugesellschaft, Darmstadt,Germany No Drawing. Application March 9, 1959 I Serial N0. 797,874

Claims priority, application Germany May 6, 1958 1 Claim. (Cl. 260294.8)

The present invention relates to a novel sulfur containing derivative ofisonicotinic acid-hydrazide, namely,

fl ethylsulfinyl-ethylsulfinybacetaldehyde-isonicotinic acid,

hydrazone of the formula and the method of its preparation.

German Patent No. 926,248 discloses the preparation of an activetuberculostatic derivative of pyridine-4-car boxylic acid hydrazide bycondensing B-methylmercaptopropionaldehyde with isonicotinic acidhydrazide and, if desired, converting the resultingp-methylmercaptopropylidene hydrazide to the corresponding sulfoxide bytreatment with an oxidizing-agent. a

The compounds of such patent are of the following structural formulae vUniteSttes Patent 2,927,926 Patented" Mar. 8,19%!

"ice

is used as a starting material can be prepared by. reacting bromacetalwith the corresponding mercaptan and by 'drolysing the resultingfl-ethylmercapto-ethylmercaptoacetal to the aldehyde.

The conversion of the sulfur the usual oxidizing agents employed foroxidizing thioethers to sulfoxides. tained when hydrogen peroxideisemployed as the oxidizing agent.

The ,8-ethylsulfinyl-ethylsulfinyl acetaldehyde-isonicotin- 1 ie acidhydrazone according to the inv ention has a particularly advantageoustherapeutic index; itstoxicity,

invention is useful as a chemotherapeutic agent for. com.-

ic acidhydrazone is to be used in combatting tuber-' culosisin'substanti'allyQ the samemanner'as the parent The novel isonicotinicacid hydrazide derivative according to the invention which differs fromthese known derivatives in the length of side chains, as well as in theprovision of two sulfur atoms therein instead of one, has

been found not only to possess very good tuberculostatic activity butalso additional advantageous pharmacological properties, particularly,in that it is especially well tolerated incomparison to the simpleisonicotinic acid hydrazide, as well as the compounds of German PatentNo. 926,248.

The novel sulfur containing isonicotinic acidjderivative according tothe invention can be produced by condensing isonicotinic acid hydrazidewith fi-ethylrnercaptoethylmercapto-acetaldehyde and subsequentlyoxidizing the thioether groups of the resulting condensation productwith an oxidizing agent normally employed to oxidize thioether groups tosulfoxide groups to producep-ethylsulfinylethylsulfinyl-acetaldehyde-isonicotinic acid hydrazone.This compound can also be produced by first oxidizing,8-ethylmercapto-ethylmercapto-acetaldehyde to produce/3-ethylsulfinyl-ethylsulfinyl-acetaldehyde and condensing thepreoxidized compound with isonicotinic acid hydrazide. Unexpectedly,the' acetaldehyde group is not attacked during the preoxidation and alsothesulfoxide group, is not attacked under the conditions employed forthe condensation. The condensations of isonicotin'ic acid hydrazide withfl-ethylmercapto-ethylmercapto-acetaldehyde and withB-ethylsulfinyl-ethylsulfinyl-acetaldehyde proceed smoothly to producethe corresponding hydrazones which crystallize well. a l :f p I The5-ethylmercapto-ethylmercapto acetaldehyde which compound, isonicotinica'cidhydrazide. I

The following examples will serve to illustrate the prep aration of thenovel compound according to the invention.

Example 1 .l( a);A mixture of46 g. of sodium'in 920cc. of absolutealcohol and 244 g. of p-ethylmercapto ethylmercaptan Was heated toboiling and 394g. of bromacetal added thereto slowly while stirring; Themixture was .35 then boiled for} hours under reflux and thereafterallowed to stand overnight. The sodium bromide precipitate off and thefiltrate boiled down undervacuum. The residue was dissolved in ether andthe'ether solution washed and dried and' the ether boiled off undervacuum.

The residue obtained ,was fractionated under vacuum. 'Thefi-ethylme'rcapto-ethylmercapto-acetal boiled at 137- u 138" C. at apressure of 1.2 mm. Hg. 347 g. of the 'fl-ethyhnercapto-ethylmercaptoacetal were shaken for 18 hours at room temperature with 3470 7 cc. of10% H 80 After extraction with ether, washing and drying, the productwas fractionated under vacuum. The,8-ethylmercapto-ethylmercapto-acetaldehyde boiled at 111-112 Get apressure of 0.6 mm. Hg.

(b) 214 g. of the B-ethylm'erCapto-ethylmercapto-acetaldehyde wereintroduced with stirring into a solution of 179 g. of isonicotinic acidhydrazide in 900 cc. of water warmed to 40 C. The mixture was stirred atroom temperature and under ice cooling. The precipitate was filtered oilon a suction filter, washed with water and recrystallized from methylacetate. The ,B-ethylmercaptuethylmercapto-acetaldehyde-isonicotinicacid hydrazone formed colorless crystals having a melting point of (c)188 g. of 30% hydrogen peroxide were added to a solution of 250 g. ofB-ethylmercapto-ethylmercaptoacetaldehyde-isonicotinic acidhydrazone in1250 cc. of

. alcohol, taking care that the temperature of the mixture did'not riseabove 50f After 3 hours stirring at room temperature and standingovernight, the mixture was boiled down under vacuum.B-Ethylsulfinyl-ethylsulfinyl-acetaldehyde-isonicotinic" acid hydrazoneor" a melting point of 158-159 C. was} obtained from the residue byrecrystallization from absolute alcohol.

Example 2 i 147 g. of 30% hydrogen peroxide were introduced with: Vstirring into a'solution of 101 g. of13-ethylmercaptoethylmercapto-acetaldehyde in 505 cc. of alcoholwhile.-.

containing compounds into the corresponding sulfoxides can becarried-outwith 7 Especially good results are 'obcooling with ice insuch a manner that the temperature We claim: 1

did not rise above 40 C. The mixture was stirred forfl-Ethylsulfinyl-ethylsulfinyl acetaldehycle isonicotinic a further 3hours and then allowed to stand for 16 hours. acid hydrazone of thestructural formula Thereafter, a solution of 84.5 g. of isonicotinicacid hydiazide in 7425 cc. of water were added and the mixture 5 NNEN=CHCHQSO-GHg-OHz-SO-CzH; stirred for another half hour. The mixturewas then 7' boiled down under vacuum. The residue upon recrys-References Cited in the fil f this patent tallization from 850 cc. ofabsolute alcohol yielded 135 g.

of B-ethylsulfinyl-ethylsulfinyl-acetaldehyde-isonicotinic UNITED STATESPATENTS acid hydrazone having a melting point of 157-158" C. 102,734,905 Zirna et a1. Feb. 14, 1956

